In 2011, it is estimated that there will be 69,250 new bladder cancer cases in the United States, resulting in 14,990 deaths. Most cases (70-80%) present with nonmuscle-invasive bladder cancer (NMIBC) [1, 2]. Intravesical bacillus Calmette-Guerin (BCG), which elicits a nonspecific local immune response, is considered the standard first-line treatment. However, over 50% of NMIBC will recur. Several chemotherapeutics have been explored in the second-line setting with only limited efficacy, forcing many patients into a radical cystectomy. Because of high disease recurrence and morbidity, the cost per bladder cancer patient is among the highest of all cancers. Thus, the development of an effective molecularly targeted intravesical therapy is highly desirable. Inhibition of the mTOR signaling pathway is a promising therapy for bladder cancer [3]. In a genetically engineered mouse bladder cancer model that recapitulates the human disease (developed by our collaborators at Columbia University), mTOR expression increased with disease progression, and the mTOR inhibitor rapamycin effectively prevented tumor progression when administered intravesically [4]. Furthermore, rapamycin was found to potentiate the induction of a BCG-mediated immune response in mice [5]. Thus, we believe that intravesical therapy with rapamycin may have significant therapeutic value in the treatment of NMIBC as a rational molecularly targeted therapy. A novel injectable nanoparticle albumin-bound rapamycin was developed (nab-rapamycin) and in various xenograft tumor models, nab-rapamycin decreased downstream signaling and showed excellent efficacy [6-8]. In a phase 1 clinical study, intravenous nab-rapamycin was safe with evidence of responses and stable disease in a variety of solid tumors [internal data]. nab-rapamycin is in the process of being licensed to AADi, LLC, a start-up company, which is the applicant for this grant. We propose to conduct a combined phase 1/2 clinical trial to assess safety, toxicity, and efficacy of local intravesical administration of nab rapamycin in patients with NMIBC that have failed BCG treatment. Our specific aims are: Phase I portion - (1) in a clinical phase 1 study, establish safety and maximum tolerated dose of intravesical nab-rapamycin, (2) in a genetically engineered mouse bladder cancer model, evaluate efficacy of the combination of intravesical nab-rapamycin and BCG; Phase II portion - (3) in patients, evaluate blood and bladder tissue levels of nab-rapamycin, (4) evaluate potential predictive clinical biomarkers, (5) evaluate efficacy/safety in a clinical phase 2 study of single agent nab-rapamycin, and (6) evaluate efficacy/safety in a phase 2 combination with BCG. This proposal will present a unique opportunity to develop the first targeted molecular therapy with nab- rapamycin for intravesical treatment of bladder cancer. Our ultimate goal is to seek FDA approval. PUBLIC HEALTH RELEVANCE: With approximately 70,000 new bladder cancer cases in the United States, and almost 15,000 deaths every year and because of high disease recurrence and morbidity, the cost per bladder cancer patient is among the highest of all cancers. Non-muscle invasive bladder cancer (NMIBC) is a recurrent disease and an effective molecularly targeted intravesical therapy especially after failure of first line therapy is highly desirable as there are not proven effective options for patients in this setting. The relevance of this proposal lies in its potential to provide better outcomes in patients with NMIBC that have failed standard therapies.